Combination containing sgc stimulators and mineralocorticoid receptor antagonists

ABSTRACT

The present invention relates to the combination of stimulators of soluble guanylate cyclase (sGC stimulators) with mineralocorticoid receptor antagonists (MR antagonists) and to the use of the combination for the treatment and/or prophylaxis of cardiac and cardiovascular disorders, of renal and cardiorenal disorders, of pulmonary and cardiopulmonary disorders and also for the treatment and/or prophylaxis of fibrotic disorders.

The present invention relates to the combination of stimulators ofsoluble guanylate cyclase (sGC stimulators) with mineralocorticoidreceptor antagonists (MR antagonists) and to the use of the combinationfor the treatment and/or prophylaxis of cardiac and cardiovasculardisorders, of renal and cardiorenal disorders, of pulmonary andcardiopulmonary disorders and also for the treatment and/or prophylaxisof fibrotic disorders.

The entire body function of humans and animals is controlled andmaintained by regulatory circuits. For their part, these physiologicalregulatory circuits comprise cascade systems of endogenous hormones,enzymes and receptors. These regulatory circuits are linked to oneanother and centrally controlled. Pathophysiological changes in thebody, but also external effects such as climate, stress, food componentsincluding medicaments, have a direct effect on these regulatorycircuits. Reduced or excessive activities of individual components ofthese cascades and regulatory systems can be compensated bycounteracting by means of feed-back or else feed-forward mechanisms.Short-term counteracting, e.g. by compensatory release of a certainendogenous hormone, is thus vital for maintenance of body function inemergency situations (e.g. in the case of injuries). However, long-term,permanent compensatory counterregulation may also have fatalconsequences for the entire organism.

Most therapeutic approaches for treating disorders of the cardiac andcardiovascular system, the renal and cardiorenal system or the pulmonaryand cardiopulmonary system and fibrotic disorders intervene in one ofthe regulatory systems mentioned. This may be associated with thedisadvantage that, owing to compensatory counterregulation of the body,there is desensitization even after a short time, and the desired effectis no longer obtained, or reduced, thus requiring the use of higherdosages, inter alia. This is associated with disadvantages such as ahigher risk of side-effects.

It is the object of the present invention to provide combinations ofpharmaceutically active substances which act on more than one regulatorycircuit and which can be employed for the treatment of cardiac andcardiovascular disorders, of renal and cardiorenal disorders, ofpulmonary and cardiopulmonary disorders and fibrotic disorders.

One of these essential regulatory systems mentioned above is the reninangiotensin aldosterone system (RAAS). This is a central cascade systemof hormones and enzymes which control salt and water balance and thusthe blood pressure of the body. In cases of lack of salt and fluid or adrop in blood pressure, the hormone renin is formed in and secreted byspecial kidney cells. Renin cleaves angiotensinogen, which is formed inthe liver, to angiotensin I, whereas the angiotensin conversion enzyme(ACE) transforms angiotensin I into angiotensin II. Angiotensin II haspotent vasoconstrictive and thus hypertensive effects and stimulates theformation of the steroid hormone aldosterone in the adrenal cortex.Aldosterone promotes the re-uptake of sodium from the urine into theblood, which increases blood volume.

The specific effects of angiotensin II are mediated by correspondingextracellular receptors (angiotensin receptor, AT-R) which are expressedon target cells of the cardiovascular system. In contrast, the specificeffects of aldosterone are mediated via an intracellular receptor, thealdosterone or mineralocorticoid receptor (MR). In addition to theircentral importance in salt, water and blood pressure regulation, bothangiotensin II and aldosterone have direct pro-inflammatory andpro-fibrotic properties. Both hormones play an essential role, inparticular in the ‘remodeling’ of heart, kidneys and vessels induced,for example, by myocardial infarction or acute kidney failure: thus, forexample, aldosterone stimulates the storage of collagen proteins in theheart muscle, which may result in increased stiffness and thereforereduced functionality long-term.

Aldosterone and angiotensin II form a classic feed-forward regulatorycircuit: In addition to potassium, angiotensin II is the most importantstimulus for the release of aldosterone from the adrenal gland, andconversely aldosterone in heart tissue and blood vessels stimulates theproduction of ACE, i.e. the enzyme which generates, from the precursorangiotensin, angiotensin II.

The pathopyhsiological effects of angiotensin II and aldosterone can bereduced by appropriate inhibitors of ACE, the AT-R and the MR; however,these singular blockades are subject to the above-mentioned feed-backcompensation mechanisms, i.e. a blockade of the mineralocorticoidreceptor leads to compensatory release of aldosterone, similar to how anAT-R blockade leads to an increase of angiotensin II.

Long-term compensatory mechanisms play a special role in the clinicallyrelevant ‘aldosterone escape’ phenomenon: Since the release ofaldosterone represents the last step in the RAAS cascade, it has beenbelieved for a long time that the blockade of the initial RAAS key stepssuch as ACE activity or the AT-R would be sufficient to also prevent thelast step, i.e. aldosterone formation and release in the adrenal gland.However, the RESOLVD study (McKelvie et al., Circulation 1999; 100;1056-1064) found that both under singular ACE or AT-R blockade and underdual ACE/AT-R blockade the aldosterone plasma level in patients withheart failure is reduced compared to baseline for the first 17 weeks oftreatment, but after 43 weeks baseline is even exceeded. The results ofthis study confirm that prevention of binding of aldosterone to themineralocorticoid receptor in addition to the angiotensin blockade is ofenormous clinical relevance.

MR antagonists (such as the steroidal compounds spironolactone,canrenone/canrenoate and eplerenone, and also more recent non-steroidalMR antagonists such as MT-3995 according to the compound of the formula(VI), CS-3150 according to the compound of the formula (V), LY2623091,PF-03882845 according to the compound of the formula (XXXII) andfinerenone, according to the compound of the formula (IV)) counteractaldosterone-mediated sodium retention in the kidneys (natriureticeffect). Thus, MR antagonists lead to increased sodium excretion, whichis a proven therapeutic concept for hypertensive patients and/orpatients suffering from heart failure and/or kidney failure. However, MRantagonists can unfold their natriuretic action only in kidney segmentsin which aldosterone also exerts its physiological action via the MR.These are in particular the late distal tubulus and collecting ductsections involved in sodium re-resorption only to a limited extent,whereas most of sodium secretion and re-resorption takes place inproximal tubulus sections.

However, in addition to the RAAS there are also other very importantregulatory systems, one of them being the nitric oxide (NO) cyclicguanosine monophosphate (cGMP) and phosphodiesterase (PDE) signallingpathway (NO/cGMP path). An increase in blood pressure and the resultingshear forces on the endothelial cells in blood vessels leads to enzymesin endothelial cells, but also in nerve endings, i.e. NO synthases (NOS)forming NO from L-arginine. This NO is gaseous and diffuses through thecell membranes into various target cells, in particular into cells ofthe vascular musculature. There, it binds to the haem group in solubleguanylate cyclase (sGC), a heterodimeric intracellular haem proteinconsisting of an alpha and a beta subunit. NO bindung activates theenzyme, which then catalyses the transformation of guanosinetriphosphate (GTP) into cGMP. This cGMP is an important second messengermolecule and binds to a large number of intracellular proteins, amongothers cGMP-dependent protein kinases (G kinases). Via phosphorylationof various target proteins, e.g. potassium channels, G kinases mediatelowering of the intracellular calcium concentration, which triggersrelaxation of the vascular musculature, for example. Accordingly, viastimulation of the sGC/cGMP path, NO has vasodilatory and thushypotensive action. In addition, numerous other actions of cGMP havealso been described, such as, for example, antithrombotic, antifibroticor anti-inflammatory action. However, on a molecular level these actionsare less well understood than vasodilation, and they have not yet beenelucidated completely. NO/cGMP signal cascade and the actions of cGMPare terminated by degradation of cGMP to ineffective GMP. This step, thehydrolysis of the cyclic phosphate ring and the formation of 5″GMP, iscatalysed by phosphodiesterases (PDE). The PDEs are a large family ofenzymes of currently eleven identified members and more than 100different splicing variants. The different PDEs differ mainly withrespect to tissue specificity (PDE6, for example, is expressedexclusively in the eye), substrate specificity (e.g. cAMP- orcGMP-specific) and regulation (e.g. via calcium/calmodulin or cyclicnucleotides). Specific cleavage of cGMP is effected mainly by PDEs oftype 5 (PDE5), 6 (PDE6) and 9 (PDE9). (cf. reviews about the NO/cGMP/PDEsignalling pathway, e.g. Conti & Beavo 2007, Schmidt et al. (editors)2009; Stasch et al. 2011, Derbyshire and Marietta 2012, Monica et al.2016).

With a view to the great importance of the NO/cGMP signalling pathwayfor physiological regulation and maintenance of body functions, inparticular for the function of the cardiac and cardiovascular system,the vascular system, kidney function or the lungs and cardiopulmonaryfunction, but also of antifibrotic effects, a number of pharmaceuticalswhich intervene at various important switching points in this signallingpathway have been investigated and developed. This was all the morenecessary since it is known that various disorders of the organ systemsmentioned above are associated with reduced NO formation, which leads toan inadequate cGMP supply and could be one of the underlyingpathomechanisms in the development of cardiac and cardiovascular, renal,pulmonary and fibrotic disorders.

For example, the use of nitrates and NO donors in the treatment ofangina pectoris, both for suppressing acute episodes and for theprophylaxis of episodes has been known for a long time. Enzymatically ornon-enzymatically, these compounds released NO which can then bind tosGC, leading to elevated cGMP concentrations. However, in addition tothe kinetic limitations of these compounds, it is mainly an increasedformation of free radicals with potential vessel- and organ-damagingeffects and the development of tachyphylaxia which limit the therapeuticpotential significantly.

Accordingly, more recent developments were focussed inter alia oninhibiting cGMP degradation by inhibiting specific PDEs, in particularinhibiting PDES. The development of potent and selective PDES inhibitorssuch as, for example, sildenafil, vardenafil or tadalafil, once moredemonstrated the effectiveness of this signalling pathway for regulatingvascular tone. This was followed by clinical approval of preparationsfor the treatment of erectile dysfunction (ED), of pulmonary arterialhypertension (PAH) and of benign prostate hyperaplasia (BPH). Moreover,these compounds are also clinically trialled for use for cardiac andcardiovascular disorders and for renal disorders. Again, thisdemonstrates the ubiquitous significance of this NO/cGMP signallingpathway and underlines the broad application potential of thesecGMP-elevating compounds. However, treatment options with PDE5inhibitors are limited as they require a sufficiently high endogenouscGMP concentration in order to be active which is then protected againstdegradation by the compounds. In the case of many disorders including inparticular cardiac and cardiovascular disorders or lung disorders,however, endogenous NO production and thus also cGMP formation is atleast partially impaired. This is why PDE5 inhibitors are not equallyeffective in all patients and why there are also treatment-resistantpatients, e.g. in cases of erectile dysfunction or pulmonaryhypertension.

To overcome this limitation of both nitrates and PDES inhibitors, therehave been attempts of direct pharmacological stimulation of sGC.Firstly, this is to avoid the NO-dependent free-radical formation of thenitrates, but secondly, this is also to avoid dependence of the efficacyon the cGMP produced, as described for PDES inhibitors. Accordingly,investigation and development of sGC stimulators and sGC activatorsrepresents a milestone in the pharmacology of the NO/cGMP signallingpath. These two compound classes, sGC stimulators and sGC activators,stimulate sGC independently of NO and lead to an NO-independentproduction of cGMP. In addition, however, these compound classes alsoact synergistically (sGC stimulators) and additively (sGC activators) toendogenously formed NO. As far as is currently known, the maindifference is sGC binding. sGC is a heterodimeric protein formed by analpha and a beta subunit; the latter carries the NO-binding haem group.The sGC stimulators bind to the alpha subunit of non-oxidized andhaem-containing sGC and cause direct NO-independent formation of cGMP(Stasch et al. (A) 2001; Stasch & Hobbs 2009). In contrast, the sGCactivators bind to the beta subunit of oxidized and haem-free sGC,activating it, and thus leading to NO-independent formation of cGMP(Stasch et al. (B) 2001, Schmidt et al. 2009). This principal differenceis very well established for in vitro conditions; however, understandingof the physiological and pathophysiological consequences of the presenceof haem-containing and oxidized haem-free sGC and the resultingtreatment potential of these compound classes is still incomplete.Nevertheless, the pharmacological utility of sGC stimulators and sGCactivators has been demonstrated in numerous preclinical models and fornumerous different indications, in particular in the field of cardiacand cardiovascular disorders, of renal and cardiorenal disorders, ofpulmonary and cardiopulmonary disorders (Evgenov et al. 2009, Stasch etal. 2011). This was also confirmed in clinical studies, and accordinglyin 2013 the sGC stimulator riociguat was approved for the treatment ofpulmonary arterial hypertension (PAH) and of chronic thromboembolicpulmonary hypertension (CTEPH) (Ghofrani et al. (A), Ghofrani et al. (B)2013, 2013 Hambly & Granton 2015). In addition, the sGC stimulatorvericiguat is in phase II/III for the treatment of heart failure (Pieskeet al. 2014, Gheorghiade et al. 2015). These examples also confirmclinically the broad possible use of sGC stimulators and sGC activatorsin the field of treatment and/or prophylaxis of cardiac andcardiovascular disorders, of renal and cardiorenal disorders and ofpulmonary and cardiopulmonary disorders. Moreover, preclinically,antifibrotic action of sGC stimulators and sGC activators wasdemonstrated convincingly.

In principle, a distinction is made between MR antagonists (MRAs) havinga steroidal skeleton and those having a non-steroidal skeleton.Steroidal MRAs such as spironolactone or its active metabolite kanrenoneinteract not only with the MR, but also with the homologous androgen andprogesterone receptors. These interactions may result in unwantedeffects on sexual hormone metabolism such as gynecomasty, dysmenorrhoeaand loss of libido. Non-steroidal MRAs such as finerenone interactspecifically with the MR, so corresponding side-effects possiblyresulting from interactions with other steroid hormone receptors are notto be expected.

Examples of steroidal mineralocorticoid receptor antagonists are (thesubject-matter disclosed in the publications below with respect to thesteroidal MR antagonists hereby also forms part of the subject-matter ofthe disclosure of the present application):

spironolactone (7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17,β-carbolacto-7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17, β-carbolactone)of the formula (I)

which is known from the literature and is already commercially availableas a medicament, among others under the tradenames Aldactone,Jenasprion, Asyrol, Spirobene, Verospiron, Xenalon,eplerenone (epoxymexerenone) of the formula (II)

which is known from the literature and is already commercially availableas a medicament, among others under the tradename Inspra,kanrenone(10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-17,5′-oxolane]-2′,3-dione)of the formula (III)

which is an active metabolite of spironolactone, is known from theliterature and is already commercially available as a medicament, amongothers under the tradenames Contaren, Luvion and Phanurane. Kanrenone isalso known and commercially available as the potassium salt potassiumkanrenoate.

Examples of non-steroidal mineralocorticoid receptor antagonists are(the subject-matter disclosed in the publications below with respect tothe non-steroidal MR antagonists hereby also forms part of thesubject-matter of the disclosure of the present application):

finereneone((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide),as a selective antagonist, based on a dihydropyridine skeleton, of theformula (IV)

which is described in DE 10 2007009494 A1 and WO 2008 104 306 A2,esaxerenone(1-(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide) of the formula (V)

which is disclosed in WO2006/012642,apararenone(N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanesulfonamide)of the formula (VI)

which is disclosed in WO07/089034,PF-03882845((3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid) of the formula (XXXII)

which is disclosed in the following publications:Meyers, M. J., Arhancet, G. B., Hockerman, S. L., Chen, X., Long, S. A.,Mahoney, M. W., Rico, J. R., Garland, D. J., Blinn, J. R., Collins, J.T., Yang, S., Huang, H. C., McGee, K. F., Wendling, J. M., Dietz, J. D.,Payne, M. A., Homer, B. L., Heron, M. I., Reitz, D. B., Hu, X., 2010.Discovery of (3S, 3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3, 3a,4, 5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), anorally efficacious mineralocorticoid receptor (MR) antagonist forhypertension and nephropathy. J. Med. Chem. 53, 5979-6002,(R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinicacid of the formula (VIII)

which is disclosed in the following publications:Casimiro-Garcia A, Piotrowski D W, Ambler C, et al. Identification of(R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinicacid, a highly potent and selective nonsteroidal mineralocorticoidreceptor antagonist. J Med Chem 2014; 57:4273-4288,MR antagonists based on an arylsulfonamide structure, such as thosedisclosed in Futatsugi K, Piotrowski D W, Casimiro-Garcia A, et al.Design and synthesis of aryl sulfonamide-based nonsteroidalmineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013;23:6239-6242,KBP-5074, which is disclosed in US2015/0126501,(S)—N-{3-[1-cyclopropyl-1-(2,4-difluorophenyl)ethyl]-1H-indol-7-yl}methanesulfonamide,which is based on an indole skeleton, of the formula (IX)

which is disclosed in the following publications:Bell M G, Gernert D L, Grese T A, Belvo M D, Borromeo P S, Kelley S A,Kennedy J H, Kolis S P, Lander P A, Richey R, Sharp V S, Stephenson G A,Williams J D, Yu H, Zimmerman K M, Steinberg M I, Jadhav P K.(S)—N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide:a potent, nonsteroidal, functional antagonist of the mineralocorticoidreceptor. J Med Chem. 2007; 50:6443-6445.Bisaryloxinidoles, which are disclosed in Neel D A, Brown M L, Lander PA, Grese T A, Defauw J M, Doti R A, Fields T, Kelley S A, Smith S,Zimmerman K M, Steinberg M I, Jadhav P K. 3,3-Bisaryloxindoles asmineralocorticoid receptor antagonists. Bioorg Med Chem Lett. 2005;15:2553-2557,and also MR antagonists based on an oxazolidinedione skeleton, which aredisclosed in the following publications:Yang C, Shen H C, Wu Z, et al. Discovery of novel oxazolidinedionederivatives as potent and selective mineralocorticoid receptorantagonists. Bioorg Med Chem Lett 2013; 23:4388-4392. Cox J M, Chu H D,Yang C, et al. Mineralocorticoid receptor antagonists: identification ofheterocyclic amide replacements in the oxazolidinedione series. BioorgMed Chem Lett 2014; 24:1681-1684. Yang C, Balsells J, Chu H D, Cox J M,Crespo A, Ma X, Contino L, Brown P, Gao S, Zamlynny B, Wiltsie J, ClemasJ, Lisnock J, Gibson J, Zhou G, Garcia-Calvo M, Bateman T J, Tong V, XuL, Crook M, Sinclair P, Shen H C. Discovery of benzimidazoleoxazolidinediones as novel and selective nonsteroidal mineralocorticoidreceptor antagonists. ACS Med Chem Lett. 2015; 6:461-465,mineralocorticoid receptor antagonists based on an indole or indazoleskeleton, as disclosed in WO2012/097744, WO2013055606, WO2013055607,WO2013055608, WO2014014794, WO2012139495.

Suitable sGC stimulators are known from the following publications (thesubject-matter disclosed in the publications below hereby also formspart of the subject-matter of the disclosure of the presentapplication):

WO2016/081668, WO2015/187470, WO2015/088885, WO2015/088886,WO2011/149921, WO2011119518, WO2010/065275, WO2016/04445, WO2016/044447,WO2016/044446, WO2016/044441, WO2015/089182, WO2014/047111,WO2014/047325, WO2013/101830, WO2012/064559, WO2012/003405,WO2011/115804, WO2014/084312, WO2012/165399, WO03/097063, WO03/09545,WO04/009589, WO03/004503, WO2007/124854, WO2008/031513, WO2008/061657,WO2010/079120, WO2010/102717, WO2011/147809, WO2012/059549,WO2012/004259, WO2012/004258, WO2012/059548, WO2012/028647,WO2012/152630, WO2014/068099, WO2014/068104, WO2012/143510,WO2012/152629, WO2013/004785, WO2013/104598, WO2013/104597,WO2013/030288, WO2013/104703, WO2013/131923, WO2014/068095,WO2014/195333, WO2014/128109, WO2014/131760, WO2014/131741,WO2015/018808, WO2015/004105, WO2015/018814, WO98/16223, WO98/16507,WO98/23619, WO00/06569, WO02/042299, WO02/092596, WO02/042300,WO02/042301, WO02/036120, WO02/042302, WO02/070461, WO2012/165399,WO2014/084312, WO2011115804, WO2012003405, WO2012064559, WO2014/047111,WO2014/047325, WO2011/149921, WO2010/065275, WO2011/119518,WO2014/144100.

Of particular importance are the following sGC stimulators having apyrazolopyridine skeleton or an imidazopyridine skeleton:

vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

which is disclosed in WO2011/147809,riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

which is disclosed in WO 03/095451,methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamateof the formula (XII)

which is disclosed in WO 03/095451,2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamineof the formula (XIII)

which is disclosed in WO00/06569,3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XIV)

which is disclosed in WO00/06568,(5R)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-D]pyrimidin-6-oneof the formula (XV)

which is disclosed in WO2014/131741,(5R)-2-[5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVI)

which is disclosed in WO2014/131760,(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVII)

which is disclosed in WO2014/131760,ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XVIII)

which is disclosed in WO2014/068099,ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XIX)

which is disclosed in WO2014/068099,ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XX)

which is disclosed in WO2014/068099,ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXI)

which is disclosed in WO2014/068099,ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXII)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIII)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIV)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXV)

which is disclosed in WO2014/068099,rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamideformiate of the formula (XXVI)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXVII)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXVIII)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXIX)

which is disclosed in WO2014/068099,ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamideof the formula (XXX)

which is disclosed in WO2014/068099,3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XXXI)

which is disclosed in WO 00/06568.

Of particular significance are furthermore the following sGCstimulators: IW-1973, IW-1701 and IW6463.

Both the RAAS and the NO/cGMP route play an important role inmaintaining homeostasis of the body and regulate important functions inthe cardiac and cardiovascular system, in the renal and cardiorenalsystem or in the pulmonary and cardiopulmonary system. The use of MRantagonists and the use of sGC stimulators as monotherapies for cardiacand cardiovascular disorders, for renal and cardiorenal disorders, forpulmonary and cardiopulmonary disorders or for fibrotic disorders hasalso been described. However, in actual fact both the proportion of thedysregulation of the two signal paths in these different disorders andthe absolute efficiency of the two mechanisms in direct comparison areunknown.

Accordingly, experiments were carried out where sGC stimulators werecompared directly with MR antagonists. This was done in order to gain aninsight into qualitative and quantitative disease relevance of these twopathomechanisms and to research the treatment paradigms derivabletherefrom.

In these experiments, combinations of MR antagonists and sGC stimulatorswere employed and also tested in direct comparison with the individualcompounds. Surprisingly, an exceptional efficacy of these combinationswas found which exceeded the efficacy of the individual components byfar and which suggests a synergistic activity of the combination of MRantagonists and sGC stimulators.

The solution to the object defined above may therefore consist in theprovision of combinations comprising at least one sGC stimulator and atleast one substance which intervenes in the RAAS system, and being ableto be used for the targeted treatment of cardiac and cardiovasculardisorders, renal and cardiorenal disorders, pulmonary andcardiopulmonary disorders and fibrotic disorders, with super-additiveeffects.

Accordingly, the invention provides inter alia a combination comprisingMR antagonists and sGC stimulators. When used under acute and inparticular under chronic conditions, the combination displays positiveeffects with respect to end organ protection of heart and kidneys,reduction of renal protein excretion, reduction of morbidity andmortality under experimental conditions. These experimental conditionsconsist of healthy animals on the one hand, or else of animals sufferingfrom hypertension, heart and/or kidney failure (e.g. transgenic reninrats), L-NAME-treated animals (e.g. transgenic renin rats+L-NAMEtreatment).

Preference is given to combinations comprising at least one sGCstimulator and at least one MR antagonist.

Preference is also given to combinations comprising at least one sGCstimulator and at least one steroidal MR antagonist.

Preference is also given to combinations comprising at least one sGCstimulator and at least one non-steroidal MR antagonist.

Preference is also given to combinations comprising at least one sGCstimulator and at least one non-steroidal MR antagonist having adihydropyridine skeleton.

Preference is also given to combinations comprising at least one sGCstimulator and at least one non-steroidal MR antagonist having an indoleor indazole skeleton.

Preference is also given to combinations comprising at least one sGCstimulator and at least one non-steroidal MR antagonist having anoxazolidinedione skeleton.

Preference is also given to combinations comprising at least one sGCstimulator and at least one steroidal MR antagonist selected from thegroup consisting of

spironolactone (7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17,β-carbolacto-7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17, β-carbolactone)of the formula (I)

eplerenone (epoxymexerenone) of the formula (II)

kanrenone(10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-17,5′-oxolane]-2′,3-dione)of the formula (III)

and its potassium salt (potassium kanrenoate).

Preference is also given to combinations comprising at least one sGCstimulator and at least one non-steroidal MR antagonist selected fromthe group consisting of

finerenone((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide)of the formula (IV)

esaxerenone(1-(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide) of the formula (V)

apararenone(N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanesulfonamide)of the formula (VI)

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid) of the formula (XXXII)

(R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinicacid of the formula (VIII)

(S)—N-{3-[1-cyclopropyl-1-(2,4-difluorophenyl)ethyl]-1H-indol-7-yl}methanesulfonamideof the formula (IX)

Preference is also given to combinations comprising at least one sGCstimulator and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator, comprising a pyrazolopyridine skeleton, and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator, comprising an imidazopyridine skeleton, and finerenone,(5)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of IW-1973 (praliciguat:1,1,1,3,3,3-hexafluoro-2-{[(5-fluoro-2-{1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)-1H-pyrazol-3-yl}pyrimidin-4-yl)amino]methyl}propan-2-olof the formula (XXXIII)),

IW-1701 and/or IW-6463 and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of

vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamateof the formula (XII)

2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamineof the formula (XIII)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XIV)

(5R)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XV)

(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVI)

(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVII)

ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XVIII)

ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XIX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXI)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIV)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXV)

rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamideformiate of the formula (XXVI)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXVII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXVIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXIX)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamideof the formula (XXX)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XXXI)

and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of

vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

(5R)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XV)

(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVI)

(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVII)

and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of

ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XVIII)

ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XIX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXI)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIV)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)ox)]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXV)

rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamideformiate of the formula (XXVI)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXVII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXVIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXIX)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamideof the formula (XXX)

and finerenone,(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Preference is also given to combinations comprising at least one sGCstimulator, comprising an pyrazolopyridine skeleton and at least one MRantagonist.

Preference is also given to combinations comprising at least one sGCstimulator, comprising an imidazopyridine skeleton and at least one MRantagonist.

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of

vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamateof the formula (XII)

2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamineof the formula (XIII)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XIV)

(5R)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XV)

(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVI)

(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVII)

ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XVIII)

ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XIX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXI)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIV)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXV)

rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamideformiate of the formula (XXVI)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXVII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXVIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXIX)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamideof the formula (XXX)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XXXI)

and at least one steroidal MR antagonist.

Preference is also given to combinations comprising at least one sGCstimulator selected from the group consisting of

vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamateof the formula (XII)

2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamineof the formula (XIII)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XIV)

(5R)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XV)

(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVI)

(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneof the formula (XVII)

ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XVIII)

ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XIX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XX)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXI)

ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXIV)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXV)

rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamideformiate of the formula (XXVI)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXVII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer B) of the formula (XXVIII)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide(enantiomer A) of the formula (XXIX)

ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamideof the formula (XXX)

3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridineof the formula (XXXI)

and at least one non-steroidal MR antagonist.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one non-steroidal MR antagonist.

Particular preference is given to combinations comprising the sGCstimulator riociguat (methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)of the formula (XI)

and at least one non-steroidal MR antagonist.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one non-steroidal MR antagonist based on a dihydropyridineskeleton.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one non-steroidal MR antagonist based on an indole orindazole skeleton.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one non-steroidal MR antagonist based on anoxazolidinedione skeleton.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one steroidal MR antagonist selected from the groupconsisting ofspironolactone (7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17,β-carbolacto-7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17, β-carbolactone)of the formula (I)

eplerenone (epoxymexerenone) of the formula (II)

kanrenone(10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-17,5′-oxolane]-2′,3-dione)of the formula (III)

and its potassium salt.

Particular preference is given to combinations comprising the sGCstimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and at least one non-steroidal MR antagonist selected from the groupconsisting offinerenone((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide)of the formula (IV)

esaxerenone(1-(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide) of the formula (V)

apararenone(N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanesulfonamide)of the formula (VI)

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid) of the formula (VI)

(R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinicacid of the formula (VIII)

(S)—N-{3-[1-cyclopropyl-1-(2,4-difluorophenyl)ethyl]-1H-indol-7-yl}methanesulfonamideof the formula (IX)

Very particular preference is given to the combination comprising thesGC stimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

Simultaneous blockade of binding of aldosterone to MR and of activationof soluble guanylate cyclase by sGC stimulators by the combinationaccording to the invention results in superadditive effects with regardto end organ protection, reduction of renal protein excretion andreduction of morbidity and mortality.

The invention further provides the use of MR antagonists in combinationwith sGC stimulators for the treatment of cardiac and cardiovasculardisorders such as heart failure with maintained ejection fraction orheart failure with reduced ejection fraction, treatment and/orprophylaxis of atrial fibrillation, stroke or atherosclerosis, for thetreatment of renal and cardiorenal disorders such as chronic kidneyfailure or diabetic nephropathy, of lung disorders and cardiopulmonarydisorders such as pulmonary hypertension, disorders of the centralnervous system, for the treatment and/or prophylaxis of fibroticdisorders and other disease manifestations (e.g. end organ damageaffecting brain, kidney, heart or lung).

Part of the subject matter of the present invention is a pharmaceuticalformulation comprising a combination of an MR antagonist and an sGCactivator, and also salts, solvates and solvates of the salts of thecomponents to be combined.

The components to be combined may be present as salts. Preferred saltsin the context of the present invention are physiologically acceptablesalts of the compounds to be combined. Also included are salts which arenot themselves suitable for pharmaceutical applications but can be used,for example, for isolation or purification of the compounds to becombined.

The combination according to the invention is suitable for theprophylaxis and/or treatment of various disorders and disease-relatedstates, in particular for the treatment and/or prophylaxis of cardiacand cardiovascular disorders such as heart failure with maintainedejection fraction or heart failure with reduced ejection fraction,treatment and/or prophylaxis of atrial fibrillation, stroke oratherosclerosis, renal and cardiorenal disorders such as chronic kidneyfailure or diabetic nephropathy, of lung disorders and cardiopulmonarydisorders such as pulmonary hypertension, disorders of the centralnervous system, for the treatment and/or prophylaxis of fibroticdisorders and other disease manifestations (e.g. end organ damageaffecting brain, kidney or heart).

Furthermore, the combinations according to the invention are suitablefor the prophylaxis and/or treatment of various disorders anddisease-related states, in particular for the treatment and/orprophylaxis of a disease selected from the group consisting ofhypertension, heart failure (acute and chronic), decompensated heartfailure, left ventricular dysfunction, hypertrophic cardiomyopathy,diabetic cardiomyopathy, supraventricular and ventricular arrythmias,atrial fibrillation, atrial flutter, detrimental vascular remodelling,myocardial infarction and sequelae thereof, atherosclerosis, angina(unstable or stable), renal failure (diabetic and non-diabetic), heartfailure, angina pectoris, diabetes, secondary hyperaldosteronism,primary and secondary pulmonary hypertension, glomerulonephritis,scleroderma and systemic sclerosis, glomerular sclerosis, proteinuria assequela of a primary kidney disease, renal vascular hypertension,diabetic and non-diabetic retinopathy, migraine, peripheral vasculardisease, Raynaud disease, luminal hyperplasia, cognitive dysfunction,glaucoma and stroke.

The present invention further provides for the use of the combinationsof the invention for production of a medicament for the treatment and/orprevention of disorders, especially of the aforementioned disorders.

The present invention further provides a method for the treatment and/orprevention of disorders, in particular the disorders mentioned above.

The combinations according to the invention can be used alone or, ifrequired, in combination with other active compounds. The presentinvention further provides medicaments comprising at least one of thecombinations according to the invention and one or more further activecompounds, especially for the treatment and/or prevention of theaforementioned disorders. Preferred examples of active compoundssuitable for combinations include:

-   -   active compounds which lower blood pressure, for example and        with preference from the group of calcium antagonists,        angiotensin receptor blockers (ARBs), ACE inhibitors, endothelin        antagonists, renin inhibitors, alpha-receptor blockers,        beta-receptor blockers and Rho kinase inhibitors;    -   diuretics, especially loop diuretics, and thiazides and        thiazide-like diuretics;    -   antidiabetics, for example and with preference insulin and        derivatives, sulfonylureas, biguanides, thiazolidinediones,        acarbose, DPP4 inhibitors, GLP-1 analogues or SGLT inhibitors        (gliflozin);    -   antithrombotic agents, by way of example and with preference        from the group of the platelet aggregation inhibitors, the        anticoagulants or the profibrinolytic substances;    -   active compounds which alter lipid metabolism, for example and        with preference from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors, preferred examples being        HMG-CoA reductase inhibitors or squalene synthesis inhibitors,        of ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha,        PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption        inhibitors, lipase inhibitors, polymeric bile acid adsorbents,        bile acid reabsorption inhibitors and lipoprotein(a)        antagonists;    -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds having a positive inotropic effect, for example        cardiac glycosides (digoxin), beta-adrenergic and dopaminergic        agonists such as isoproterenol, adrenaline, noradrenaline,        dopamine and dobutamine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,        3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,        vardenafil and tadalafil, and PDE 3 inhibitors such as amrinone        and milrinone;    -   natriuretic peptides, for example atrial natriuretic peptide        (ANP, anaritide), B-type natriuretic peptide or brain        natriuretic peptide (BNP, nesiritide), C-type natriuretic        peptide (CNP) and urodilatin;    -   inhibitors of endopeptidases (NEP inhibitors) such as        sacubitril, omapatrilate or AVE-7688, or in dual combination        (‘ARNIs’) with angiotensin receptor blockers (e.g. valsartan),        e.g. LCZ696;    -   calcium sensitizers, for example and with preference        levosimendan;    -   If channel blockers, for example and with preference ivabradine;    -   myosin activators, for example and with preference omecamtiv        mecarbil;    -   inhibitors of human neutrophil elastase (HNE), for example        sivelestat or DX-890 (Reltran);    -   compounds which inhibit the signal transduction cascade, for        example tyrosine kinase inhibitors, especially sorafenib,        imatinib, gefitinib and erlotinib; and/or    -   compounds which influence the energy metabolism of the heart, by        way of example and with preference etomoxir, dichloroacetate,        ranolazine or trimetazidine

In a preferred embodiment of the invention, the combination of theinvention is administered in combination with a diuretic, by way ofexample and with preference furosemide, bumetanide, torsemide,bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide,chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamterene.

Agents which lower blood pressure are preferably understood to meancompounds from the group of calcium antagonists, angiotensin receptorblockers, ACE inhibitors, endothelin antagonists, renin inhibitors,alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors,and the diuretics.

In a preferred embodiment of the invention, the combination preparationaccording to the invention is administered in combination with anantidiabetic such as, by way of example and with preference, insulin andderivatives, sulfonylureas such as tolbutamide, carbutamide,acetohexamide, chlorpropamide, glipizide, gliclazide, glibenclamide,glyburide, glibornuride, gliquidone, glisoxepide, glyclopyramide,glimepiride, JB253 and JB558, meglitinides such as repaglinide andnateglinide, biguanides such as metformin and buformin,thiazolidinediones such as rosiglitazone and pioglitazone,alpha-glucosidase inhibitors such as miglitol, acarbose and voglibose,DPP4 inhibitors such as vildagliptin, sitagliptin, saxagliptin,linagliptin, alogliptin, septagliptin and teneligliptin, GLP-1 analoguessuch as exenatide (also exendin-4), liraglutide, lixisenatide andtaspoglutide, or SGLT inhibitors (gliflozins) such as canagliflozin,dapagliflozin and empagliflozin.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a calcium antagonist,by way of example and with preference nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an angiotensin AIIantagonist, by way of example and with preference losartan, candesartan,valsartan, olmesartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an ACE inhibitor, byway of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an endothelinantagonist, by way of example and with preference bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a renin inhibitor, byway of example and with preference aliskiren, SPP-600, SPP-635, SPP-676,SPP-800 or SPP-1148.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an alpha-1 receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a beta receptorblocker, by way of example and with preference propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a Rho kinaseinhibitor, by way of example and with preference fasudil, Y-27632,SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with prostanoids andprostacyclin receptor agonists, by way of example and with preferenceiloprost, beraprost, cicaprost, epoprostenol or treprostinil.

Antithrombotic agents (antithrombotics) are preferably understood tomean compositions from the group of platelet aggregation inhibitors, ofanticoagulants or of profibrinolytic substances.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a platelet aggregationinhibitor, by way of example and with preference aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a thrombin inhibitor,by way of example and with preference ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a GPIIb/IIIaantagonist, by way of example and with preference tirofiban orabciximab.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a factor Xa inhibitor,by way of example and with preference rivaroxaban (BAY 59-7939),DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux,idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021,DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a vitamin Kantagonist, by way of example and with preference coumarin.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbers, bile acidreabsorption inhibitors, lipase inhibitors and the lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the combination according tothe invention is administered with a CETP inhibitor, by way of exampleand with preference torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY78-7499 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an ACAT inhibitor, byway of example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a PPAR-gamma agonist,by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the combination according tothe invention is administered with a PPAR-delta agonist, by way ofexample and with preference GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the combination according tothe invention is administered with a cholesterol absorption inhibitor,by way of example and with preference ezetimibe, tiqueside orpamaqueside.

In a preferred embodiment of the invention, the combination according tothe invention is administered with a lipase inhibitor, by way of exampleand with preference orlistat.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a polymeric bile acidadsorber, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a bile acidreabsorption inhibitor, by way of example and with preference ASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the combination according tothe invention is administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

In the preferred embodiment of the invention, the combination accordingto the invention is administered in combination with compounds havingantifibrotic action, such as, by way of example and with preference,sorafenib, regorafenib, imatinib, dasatinib, nilotinib, nintedanib,bortezomib or pirfenidone.

In the preferred embodiment of the invention, the combination accordingto the invention is administered in combination with compounds havingantiinflammatory action, such as, by way of example and with preference,cyclophosphamide, methotrexate, rapamycin, azathioproin, tocilizumab,infliximab, rituximab, adalimumab, belimumab, abatacept, SAR100842 orthalidomide derivatives.

The combinations according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

The combinations according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the combinations of theinvention rapidly and/or in a modified manner and which contain thecompounds of the invention in crystalline and/or amorphized and/ordissolved form, for example tablets (uncoated or coated tablets, forexample with enteric coatings or coatings which dissolve in a delayedmanner or insoluble coatings which control the release of thecombinations of the invention), tablets or films/wafers whichdisintegrate rapidly in the oral cavity, films/lyophilizates, capsules(for example hard or soft gelatin capsules), sugar-coated tablets,granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Preferred administration forms that may be mentioned are tablet forms(uncoated or coated tablets, for example with enteric coatings orcoatings which dissolve in a delayed manner or insoluble coatings whichcontrol the release of the combinations according to the invention),tablets which disintegrate rapidly in the mouth or films/wafers.

Parenteral administration can be accomplished with avoidance of aresorption step (for example by an intravenous, intraarterial,intracardiac, intraspinal or intralumbar route) or with inclusion of aresorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Administrationforms suitable for parenteral administration include inter aliapreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalationmedicaments (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets for lingual, sublingual or buccaladministration, films/wafers or capsules, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, dustingpowders, implants or stents.

Preference is given to oral or parenteral administration, oraladministration being more preferred. Particular preference is given tooral administration by means of tablet form.

The combinations according to the invention can be converted to theadministration forms mentioned. This can be accomplished in a mannerknown per se by mixing with inert, non-toxic, pharmaceutically suitableexcipients. These excipients include inter alia carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulfate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g.

antioxidants, for example ascorbic acid), colourants (e.g. inorganicpigments, for example iron oxides) and flavour and/or odour correctors.

In the combinations according to the invention, the components may beadministered together or successively or separately in a combined unitdosage form or in two separate unit dosage forms. The unit dosage formmay also be a fixed combination.

A therapeutically effective amount of each component of the combinationaccording to the invention may be administered simultaneously orsequentially in any sequence.

In one embodiment, the components may be present in a so-calleddelayed-release formulation in which the release of the componentsaccording to the invention takes place at different times. By way ofexample, mention may be made of a tablet with delayed-dissolutioncoatings, each of which contains one or more components according to theinvention.

If the components of the combination according to the invention areadministered in separate unit dosage forms, the MR antagonists and sGCstimulators can each be provided, for example, as a capsule or tablet.

In the case of oral administration, the dosage of finerenone accordingto the compound of the formula (IV) is for example about 1 to 100 mg od,preferably about 2.5 to 50 mg od and very particularly preferably 10 to40 mg od.

In the case of oral administration, the dosage of vericiguat accordingto the compound of the formula (X) is for example about 0.5 to 50 mg od,preferably about 1 to 15 mg od and very particularly preferably 1.25 to10 mg od.

It may nevertheless be necessary in some cases to deviate from thestated amounts, and specifically as a function of body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time at which or interval over which administrationtakes place. Thus in some cases it may be sufficient to manage with lessthan the aforementioned minimum amount, while in other cases the upperlimit mentioned must be exceeded. In the case of administration ofgreater amounts, it may be advisable to divide them into severalindividual doses over the day.

The invention also relates to the combination of separate pharmaceuticalcompositions in kit form. This is a kit comprising two separate units: apharmaceutical composition of at least one MR antagonist and apharmaceutical composition of at least one sGC stimulator.

The invention also relates to a preferred kit form comprising two units:a pharmaceutical composition comprising at least one MR antagonist and apharmaceutical composition comprising at least one sGC stimulator.

The kit is particularly advantageous if the separate components have tobe administered in different dose forms or are administered in differentdose intervals.

Working Examples of Pharmaceutical Compositions

The compounds of the invention can be converted to pharmaceuticalpreparations as follows:

Tablet: Pharmaceutical formulation of finerenone(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)

A granular solution of the compound of the formula (IV) in crystallineform in micronized form, hypromellose 5 cP and sodium lauryl sulfate wasprepared in purified water.

Microcrystalline cellulose, lactose monohydrate and croscarmellosesodium were mixed (premix) in a container or a fluidized bed granulator.

The premix and the granular solution were granulated in the fluid-bedgranulator.

The lubricant magnesium stearate was added after which the granulate wasdried and sieved. A ready to press mixture was thus prepared.

The ready to press mixture was compressed to give tablets using a rotarytablet press.

A homogeneous coating suspension was prepared from hypromellose, talc,titanium dioxide, yellow iron oxide, red iron oxide and purified water.The coating suspension was sprayed onto the tablets in a suitablecoating device.

Composition Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb [mg] [mg][mg] [mg] [mg] [mg] [mg] Compound of the formula (IV) in 1.25 2.50 5.007.50 10.00 15.00 20.00 micronized Excipients Microcrystalline 73.8072.50 69.90 67.30 64.70 62.00 59.30 cellulose Croscarmellose 4.50 4.504.50 4.50 4.50 4.50 4.50 sodium Hypromellose 5 cP 4.50 4.50 4.50 4.504.50 4.50 4.50 Lactose monohydrate 45.00 45.00 45.00 45.00 45.00 42.5040.00 Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90 Sodiumlauryl sulfate 0.05 0.10 0.20 0.30 0.40 0.60 0.80 Weight (uncoated130.00 130.00 130.00 130.00 130.00 130.00 130.00 tablets) Film-coatingHypromellose 5 cP 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336Titanium dioxide 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 Talc0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 Yellow iron oxide0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 Red iron oxide 0.00720.0072 0.0072 0.0072 0.0072 0.0072 0.0072 Weight (film- 6.0000 6.00006.0000 6.0000 6.0000 6.0000 6.0000 coating) Weight (coated 136.00 136.00136.00 136.00 136.00 136.00 136.00 tablet)

Assessment of Physiological Efficacy

The suitability of the combinations according to the invention for thetreatment of cardiac and cardiovascular disorders and renal andcardiorenal disorders and other disorders described in the applicationcan be demonstrated in the following assay systems:

1.) In Vivo Assay for Detecting Natriuretic Activity on Conscious Ratsin Metabolic Cages

Wistar rats (body weight 250-450 g) are kept with free access to feed(Altromin) and drinking water. From approx. 72 hours before the start ofthe test, the animals receive, instead of the normal feed, exclusivelyreduced-salt feed with a sodium chloride content of 0.02% (ssniff R/M-H,10 mm with 0.02% Na, S0602-E081, ssniff Spezialdiaten GmbH, D-59494Soest, Germany). During the test, the animals are housed singly inmetabolic cages suitable for rats of this weight class (TecniplastGermany GmbH, D-82383 Hohenpeissenberg, Deutschland) with free access toreduced-salt feed and drinking water for about 24 hours. At the start ofthe test, the substance to be tested is administered into the animals'stomachs by means of gavage in a volume of 0.5 ml/kg of body weight of asuitable solvent. Control animals receive only solvent. Controls andsubstance tests are carried out in parallel on the same day. Controlgroups and substance-dose groups each consist of 6 to 8 animals Duringthe test, the urine excreted by the animals is continuously collected ina receiver on the base of the cage. The urine volume per unit time isdetermined separately for each animal, and the concentration of thesodium and potassium ions excreted in the urine is measured by standardmethods of flame photometry. The measurement intervals are typically theperiod up to 8 hours after the start of the test (day interval) and theperiod from 8 to 24 hours after the start of the test (night interval).

2.) DOCA/Salt Model

Administration of deoxycorticosterone acetate (DOCA) in combination witha high-salt diet and unilateral kidney removal in rats induceshypertension which is characterized by relatively low renin levels. Aconsequence of this endocrine hypertension (DOCA is a direct precursorof aldosterone) is, depending on the chosen DOCA concentration, cardiachypertrophy and further end organ damage, for example to the kidney,which is characterized by proteinuria and glomerulosclerosis, interalia. It is thus possible in this rat model to investigate testsubstances for the presence of an antihypertrophic and endorgan-protecting effect.

Male Sprague-Dawley (SD) rats of about 8 weeks in age (body weightbetween 250 and 300 grams) undergo left uninephrectomy. For thispurpose, the rats are anaesthetized with 1.5-2% isoflurane in a mixtureof 66% N₂O and 33% O₂, and the kidney is removed through a flankincision. “Sham-operated” animals from which no kidney is removed servelater as control animals

Uninephrectomized SD rats receive 1% sodium chloride in the drinkingwater and a subcutaneous injection of DOCA (from SIGMA, dissolved insesame oil; high dose: 100 mg/kg/wk s.c.; normal dose: 30 mg/kg/wk s.c.)injected between the shoulder blades once a week.

The substances which are to be studied for their protective effect invivo are administered by gavage or via the feed (Ssniff, Germany). Oneday before the start of the test, the animals are randomized andassigned to groups with an identical number of animals, usually n=8-15.During the entire experiment, drinking water and feed are available adlibitum to the animals. The substances (combinations) are administeredvia the feed or once a day by gavage for 4-12 weeks Animals treated inthe same way but receiving either only the solvent or the feed withouttest substance serve as placebo group.

At the end of the experiment, haemodynamic parameters (blood pressure,heart rate, inotropism [dp/dt], relaxation time [tau], maximum leftventricular pressure, left ventricular end-diastolic pressure [LVEDP])may be measured, and also the weights of heart, kidney and lung, proteinelimination and gene expression of biomarkers (e.g. BNP, brainnatriuretic peptide, plasma renin activity, angiotensin and aldosterone)by RIA, ELISA or RT/TaqMan PCR following RNA isolation from cardiac andrenal tissue determined.

3.) L-NAME-Treated Transgenic Renin Rat (TGR(mRen2)27)

The transgenic renin rat ‘TGR(mRen2)27’ is a hypertensive rat linedeveloped by Mullins and Ganten which overexpresses the Ren-2 gene ofthe mouse. Additional administration of the nitrogen monoxide synthaseinhibitor L-NAME induces endothelial dysfunction which increasesmorbidity and mortality in this model. Unless subjected to life-longantihypertensive therapy, homozygous animals die of secondarycomplications such as heart and kidney failure or stroke.

Male TGR(mRen2)27 renin rats aged 10 to 20 weeks are randomized todifferent pharmacological treatment groups and a placebo group. Inaddition, the nitrogen monoxide synthase inhibitor L-NAME isadministered via the drinking water in a concentration of 30 to 100mg/l. During the entire experiment, drinking water and feed areavailable ad libitum to the animals. The substances are administered viathe feed or daily by gavage for 4-10 weeks Animals treated in the sameway but receiving either only the solvent or the feed without testsubstance serve as placebo group. During the experiment, the systolicblood pressure is determined at regular intervals using a tail cuff, andproteinuria and urine electrolyte composition are determined bycollecting the urine in metabolic cages. At the end of the experiment,haemodynamic parameters (blood pressure, heart rate, inotropism [dp/dt],relaxation time [tau], maximum left ventricular pressure, leftventricular end-diastolic pressure [LVEDP]) are measured, and theweights of heart, kidney and lung are determined, protein eliminationand biomarkers (e.g. ANP, RIA Kit RK 005-24, Phoenix Pharmaceuticals,Inc., USA, cGMP, RIA Kit RE29075, IBL International GmbH, Hamburg,Germany, renin, angiotensin I, RIA Kit CA-1533, DiaSorin S.p.A., Italy,and aldosterone, P2714, DiaSorin S.p.A., Italy) and gene expression ofbiomarkers by RT/TaqMan PCR following RNA isolation from cardiac andrenal tissue are determined.

EXAMPLES

Cardiac and cardiovascular disorders as well as renal and cardiorenaldisorders are characterized by high patient morbidity and also highmortality. This morbidity and mortality, together with various riskfactors such as hypertension, can be reproduced very accurately in theabove-described animal model of the L-NAME-treated renin transgenic rat.Therefore, this animal model, for example, was used to investigate MRantagonists such as, for example, finerenone according to the compoundof the formula (IV) and sGC stimulators such as, for example, thecompound of the formula (X), and combinations of both:

For example, the MR antagonist finerenone, corresponding to the compoundof the formula (IV), and the sGC stimulator, corresponding to thecompound of the formula (X), were tested on their own and incombinations in TGR(mRen2)27 renin rats aged 10 to 20 weeks. Inaddition, the nitrogen monoxide synthase inhibitor L-NAME wasadministered via the drinking water in a concentration of 30 to 100mg/l. During the entire experiment, drinking water and feed wereavailable ad libitum to the animals. The substances were administereddaily by gavage for 4-10 weeks. Animals treated in the same way butreceiving only the solvent for the test substance served as placebogroup. In the test series, in addition to placebo (group A), the MRantagonist finerenone corresponding to the compound of the formula (IV)(10 mg/kg od) (group B) and the sGC stimulator corresponding to thecompound of the formula (X) (0.3 mg/kg od) (group C) on their own and acombination of finerenone corresponding to the compound of the formula(IV) (10 mg/kg od)+compound of the formula (X) (0.3 mg/kg od) (group D)were administered. In this study, 15 animals were used per group (A, B,C, D) (Table 1):

TABLE 1 Group classification, treatment, dosage employed andadministration protocol (od = once daily; bid = bidaily) and group sizeof the L-NAME-treated renin transgenic rats. Group Group size nameTreatment Dose [n] Group A placebo 15 Group B finerenone (compound ofthe  10 mg/kg od 15 formula (IV)) Group C Compound of the formula (X)0.3 mg/kg od 15 Group D finerenone (compound of the 10 mg/kg od + 15formula (IV)) + 0.3 mg/kg od Compound of the formula (X)

Mortality:

After 40% of the placebo animals had died—the study was generallyterminated once 40-50% of the placebo-treated animals had died, whichcorresponds to a survival rate of 60-50%—the study was terminated andthe survival rates of the individual treatment groups were compared toone another. It was found that, in the case of treatment with finerenonecorresponding to the compound of the formula (IV) (10 mg/kg od) on itsown or sGC stimulator corresponding to the compound of the formula (X)(0.3 mg/kg od) on its own, only 20% and 13%, respectively, of theanimals died during the study period, which corresponds to survivalrates of 80% and 87%, respectively. However, a combination of finerenonecorresponding to the compound of the formula (10 mg/kg od)+compound ofthe formula (X) (0.3 mg/kg od) prevented all cases of death throughoutthe study period and led to significant higher survival with a survivalrate of 100% over the study period (Table 2):

TABLE 2 All-cause mortality of L-NAME-treated renin- transgenic ratsduring the study period. Mortality Significance Group [%] versus Group AGroup A 40 Group B 20 Group C 13 Group D 0 **

In parallel with the complete prevention of cardiovascular andcardiorenal mortality, other parameters of cardiac, cardiovascular andrenal function were also improved. These were quantified, for example,by determining protein excretion via the kidney, or by BNP production(BNP=Brain Natriuretic Peptide) in the heart by determination of the BNPplasma concentration.

Proteinuria; Protein/Creatinine Quotient in Urine:

For determining kidney damage in patients, protein excretion in thekidney—which is markedly enhanced in patients—is used. Here, thequotient of protein excreted in the urine and creatinine excreted in theurine, the so-called protein/creatinine quotient, which can be used as aquantitative measure for the kidney damage, is determined. In the animalexperiments carried out, too, for example proteinuria, measured asprotein/creatinine quotient in urine, has already been loweredsignificantly on treatment with finerenone (10 mg/kg od) on its own orwith the sGC stimulator corresponding to the compound of the formula (X)(0.3 mg/kg od) on its own, by 58% and 51%, respectively. However, here,too, the combination of finerenone (10 mg/kg od)+compound of the formula(X) (0.3 mg/kg od) resulted in a markedly more pronounced, highlysignificant reduction of proteinuria by a total of 73% (Table 3):

TABLE 3 proteinuria (in % reduction from placebo) at the end of thestudy in L-NAME-treated renin transgenic rats. Data as mean ± SEM;*/**/***/**** = significant with p < 0.05/0.01/0.001/0.0001 (one-wayANOVA + post hoc analysis). Protein/creatine Significance Groupquotient - % of group A versus Group A Group A +/−0 + 15  Group B −58 +16 * Group C −51 + 20 * Group D −73 + 2  **

1. Combinations, comprising at least one sGC stimulator and at least onenon-steroidal MR antagonist.
 2. Combination according to claim 1,comprising the sGC stimulator vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateof the formula (X)

and(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)


3. (canceled)
 4. (canceled)
 5. (canceled)
 6. Medicament, comprising atleast one combination according to claim 1 in combination with an inert,non-toxic, pharmaceutically suitable auxiliary.
 7. Medicament,comprising at least one combination according to claim 1, in combinationwith one or more further active compounds selected from the groupconsisting of ACE inhibitors, angiotensin receptor blockers,combinations of angiotensin receptor blockers and NEP inhibitors(ARNIs), antidiabetics, betablockers, acetylsalicylic acid, diuretics,I_(f) channel blockers (ivabradin), calcium antagonists, statins,digitalis (digoxin) derivatives, calcium sensitizers, nitrates andantithrombotics.
 8. (canceled)
 9. A method for the treatment and/orprophylaxis of cardiovascular disorders, renal disorders, lungdisorders, and fibrotic disorders, in humans and animals comprisingadministering a therapeutically effective amount of a medicamentaccording to claim 6 to a human or animal in need thereof.
 10. Themethod of claim 9, wherein 10 to 40 mg of finerenone are administered.11. Kit, comprising a pharmaceutical composition comprising finerenoneand the compound of the formula (X).
 12. A method for the treatmentand/or prophylaxis of cardiac and cardiovascular disorders, renaldisorders, cardiorenal disorders, pulmonary and cardiopulmonarydisorders, and fibrotic disorders comprising administering atherapeutically effective amount of a combination of an sGC stimulatorand a non-steroidal MR antagonist to a human or animal in need thereof.13. The method of claim 12, wherein the sGC stimulator and thenon-steroidal MR antagonist are administered sequentially.
 14. Themethod of claim 12, wherein the sGC stimulator and the non-steroidal MRantagonist are administered in two separate unit dosage forms.
 15. Themethod of claim 12, wherein the sGC stimulator is vericiguat (methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate)of the formula (X)

and the non-steroidal MR antagonist is(S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (IV)


16. The method of claim 12, wherein 10 to 40 mg of finerenone areadministered.
 17. The method of claim 15, wherein the sGC stimulator andthe non-steroidal MR antagonist are administered sequentially.
 18. Themethod of claim 15, wherein the sGC stimulator and the non-steroidal MRantagonist are administered in two separate unit dosage forms.
 19. Themethod of claim 15, wherein the sGC stimulator and the non-steroidal MRantagonist are administered simultaneously.
 20. The method of claim 12,wherein the sGC stimulator and the non-steroidal MR antagonist areadministered simultaneously.